Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62

Jung, Hyun Jung; Kim, Yoon Jeong; Eggert, Simone; Chung, Kwang Chul; Choi, Kyeong Sook; Park, Sun Ah

doi:10.1016/j.expneurol.2013.07.013

Cited by 46 publications

(19 citation statements)

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“…Recent study indicated that type 1 DM [30] model induced by STZ as well as spontaneous type 2 DM [31,32] model showed overexpression of phosphorylated tau at Ser396 cite. In the present study, we also found tau hyperphosphorylation at Ser396 in hippocampus after STZ treatment in mice fed with the control diet, which further confirmed that insulin deficiency caused by STZ could increase phosphorylation of tau.…”

Section: Discussionmentioning

confidence: 99%

Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice

Zheng

Zou

et al. 2017

IJMS

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High incidence rate of Alzheimer’s disease (AD) is observed in patients with type 2 diabetes. Aggregated β-amyloid (Aβ) and hyperphosphorylated tau are the hallmarks of AD. Hyperphosphorylated tau has been detected in diabetic animals as well as in diabetic patients. Folates mediate the transfer of one carbon unit, required in various biochemical reactions. The effect of folate on tau phosphorylation in diabetic models still remains unknown. In this study, we investigated the effect and mechanism of folic acid on hyperphosphorylation of tau in streptozotocin (STZ)-induced diabetic mice. Diabetic mice induced by STZ, at the age of 10 weeks, were administered with three levels of folic acid: folic acid-deficient diet, diet with normal folic acid content, and 120 μg/kg folic acid diet for 8 weeks. Levels of serum folate and blood glucose were monitored. Tau phosphorylation, protein phosphatase 2A (PP2A) methylation, and Glycogen synthase kinase 3β (GSK-3β) phosphorylation were detected using Western blot. The S-adenosyl methionine:S-adenosyl homocysteine ratio (SAM:SAH) in brain tissues was also determined. DNA methyltransferase (DNMT) mRNA expression levels were detected using real-time PCR. Folic acid reduced tau hyperphosphorylation at Ser396 in the brain of diabetes mellitus (DM) mice. In addition, PP2A methylation and DNMT1 mRNA expression were significantly increased in DM mice post folic acid treatment. GSK-3β phosphorylation was not regulated by folic acid administration. Folic acid can reduce tau phosphorylation by regulating PP2A methylation in diabetic mice. These results support that folic acid can serve as a multitarget neuronal therapeutic agent for treating diabetes-associated cognitive dysfunction.

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Section: Discussionmentioning

confidence: 99%

Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice

Zheng

Zou

et al. 2017

IJMS

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“…Several studies have reported Tau hyperphosphorylation in rat (Li et al, 2007; Jung et al, 2011, 2013) and mouse models (Kim et al, 2009; Li et al, 2012a) of spontaneous T2DM. For example, Jung et al have reported an increase in Tau phosphorylation at the Tau-1, Thr 212 (Jung et al, 2011, 2013), Thr 231 , Ser 262 and Ser 396 (Jung et al, 2013) epitopes in the chronic Otsuka Long Evans Tokushima Fatty (OLETF) T2DM rat model, and these changes were further increased with age (Jung et al, 2013).…”

Section: Impact Of Insulin Dysfunction On Tau Phosphorylationmentioning

confidence: 99%

Insulin dysfunction and Tau pathology

Khoury

Gratuze

Papon

et al. 2014

Front. Cell. Neurosci.

110

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The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

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“…In particular, diet-induced obesity (DIO) accelerates AD-related pathology in mouse models of AD (Ho et al, 2004; Julien et al, 2010; Kohjima et al, 2010; Barron et al, 2013; Orr et al, 2014). Further, genetic models of obesity and type 2 diabetes exhibit features of AD-like neuropathology (Kim et al, 2009; Jung et al, 2013; Ramos-Rodriguez et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Obesity Accelerates Alzheimer-Related Pathology inAPOE4but notAPOE3Mice

Moser

Pike

2017

eNeuro

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Alzheimer’s disease (AD) risk is modified by both genetic and environmental risk factors, which are believed to interact to cooperatively modify pathogenesis. Although numerous genetic and environmental risk factors for AD have been identified, relatively little is known about potential gene-environment interactions in regulating disease risk. The strongest genetic risk factor for late-onset AD is the ε4 allele of apolipoprotein E (APOE4). An important modifiable risk factor for AD is obesity, which has been shown to increase AD risk in humans and accelerate development of AD-related pathology in rodent models. Potential interactions between APOE4 and obesity are suggested by the literature but have not been thoroughly investigated. In the current study, we evaluated this relationship by studying the effects of diet-induced obesity (DIO) in the EFAD mouse model, which combines familial AD transgenes with human APOE3 or APOE4. Male E3FAD and E4FAD mice were maintained for 12 weeks on either a control diet or a Western diet high in saturated fat and sugars. We observed that metabolic outcomes of DIO were similar in E3FAD and E4FAD mice. Importantly, our data showed a significant interaction between diet and APOE genotype on AD-related outcomes in which Western diet was associated with robust increases in amyloid deposits, β-amyloid burden, and glial activation in E4FAD but not in E3FAD mice. These findings demonstrate an important gene-environment interaction in an AD mouse model that suggests that AD risk associated with obesity is strongly influenced by APOE genotype.

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Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62

Cited by 46 publications

References 47 publications

Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice

Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice

Insulin dysfunction and Tau pathology

Obesity Accelerates Alzheimer-Related Pathology inAPOE4but notAPOE3Mice

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